Bacterial drug resistance is a significant current health problem throughout the world. Multiple drug resistance is being commonly seen in a number of human pathogens (see, e.g., Hiramatsu et al., J. Antimicrob. Chemother., 1998, 40, 311-313 and Montecalvo et al., Antimicro. Agents Chemother., 1994, 38, 1363-1367, and the incidence of drug-resistant hospital infections is growing at a rapid rate. For example, in some U.S. hospitals, nosocomial pathogens, such as E. faecium and Acinetobacter species, have acquired multiple resistance determinants and are virtually untreatable with current antimicrobial agents. Bacterial resistance has now reached epidemic proportions and has been attributed to a variety of abuses of antibiotic treatments, including overuse (Monroe et al., Curr. Opin. Microbiol., 2000, 3, 496-501), inappropriate dosing at sub-therapeutic levels (Guillemot et al., JAMA, 1998, 279, 365-370), and misuse as antimicrobial growth promoters in animal food (Lathers, J. Clin. Pharmacol., 2002, 42, 587-600). Moreover, the threat of bio-terrorism has provided a further impetus to develop novel classes of antibiotics, particularly ones against which it will be difficult to develop resistant bacterial strains.
The pharmaceutical scientific community is responding to this challenge by focusing on the development of new antibiotic drugs. Much of this work, however, is directed to synthesizing analogs of known drugs, such as cephalosporins and quinolones, that, while potentially useful for a short time, will inevitably also encounter bacterial drug resistance and become ineffective. Thus, therapeutically effective antimicrobial drugs that act by novel mechanisms would provide an economic as well as a human health benefit.
A series of nonpeptidic mimics of the natural antimicrobial peptides have been developed that are polymers, oligomers and small molecules comprised of non-natural building blocks. See, Tew et al., Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 5110-5116; Arnt et al., J. Polym. Sci., Part A, 2004, 42, 3860-3864; and Liu et al., Angew Chem. Int. Ed. Engl., 2004, 43, 1158-1162. Many of these compounds are significantly smaller and easier to prepare than the natural antimicrobial peptides and peptidic mimetics, with the shortest of these oligomers having molecular weights typical of small molecule drugs. They have the same mechanism of action as magainin, are highly potent and have a broad spectrum of activity, killing gram-positive, gram-negative and antibiotic-resistant pathogens. Relative to the antimicrobial peptides, the non-peptidic mimetics are significantly less toxic towards human erythrocytes, much less expensive to prepare, and more stable.
See, for example, U.S. Published Patent Appl. Nos. US 2006-0041023 A1, US 2004-0202639 A1, US 2005-0287108 A1, and US 2006-0024264 A1, and U.S. Pat. No. 7,173,102.
There is a great need for improved compositions and methods of treatment based on the use of antimicrobials that are more effective than existing agents against key ophthalmic and otic pathogens, and less prone to the development of resistance by those pathogens. In particular, there is a great need for effective compositions and methods for the treatment of otic infections, especially bacterial infections. The use of oral antibacterials to treat otic infections in children has limited efficacy and creates a serious risk of pathogen resistance to the orally administered antibacterial agent.
Thus, a need remains for improved ophthalmic and otic antimicrobial compositions, in particular, for broad-spectrum antimicrobial agents useful for the treatment of ophthalmic and otic infections that are not prone to the development of resistance by ophthalmic and/or otic pathogens and that are effective in the treatment of ophthalmic and otic pathogens that have already developed resistance to existing antimicrobial agents.